Process for the preparation of imidazopyridines

ABSTRACT

A compound of general formula (1), in which: Y denotes hydrogen, a halogen or a C1-4 alkyl group X1 and X2 denote, independently of each other, hydrogen, a halogen or a C1-4 alkoxy, C1-6 alkyl, CF3, CH3S CH3SO2 or NO2 group and R1 and R2 denote independently of each other, hydrogen or a C1-5 alkyl group, with the proviso that R1 and R2 do not both denote hydrogen, or a salt thereof is prepared by a multi-step process, the last step of which comprises reducing a compound of the general formula (6), in which Y, X1, X2, R1 and R2 are as defined above with an appropriate reducing agent, such as Zn, and, if desired, converting the compound of formula (1) thus obtained, into a salt. The products of this process are known to have useful pharmacological properties, e.g. as anxiolytics.

[0001] The present invention relates to a process for preparingimidazopyridines of the general formula (1)

[0002] in which:

[0003] Y denotes hydrogen, a halogen or a C₁₋₄ alkyl group,

[0004] X₁ and X₂ denote, independently of each other, hydrogen, ahalogen or a C₁₋₄ alkoxy, C₁₋₆ alkyl, CF₃, CH₃S, CH₃SO₂ or NO₂ group and

[0005] R₁ and R₂ denote, independently of each other, hydrogen or a C₁₋₅alkyl group, with the proviso that R₁ and R₂ do not both denotehydrogen,

[0006] or salts thereof.

[0007] The products of this process are known to have usefulpharmacological properties, e.g. as anxiolytics, see European Patent No.0 050 563. A process for preparing compounds of formula 1 is describedin U.S. Pat. No. 4,794,185, Dec. 12, 1988.

[0008] The present invention relates to a more efficient process forpreparing compounds of formula (1).

[0009] In accordance with the present invention, compounds of thegeneral formula (1) can be prepared by reacting a compound of thegeneral formula (2)

[0010] in which Y, X₁ and X₂, are as defined above with a compound ofthe general formula (3)

[0011] in which:

[0012] A denotes a halogen and B denotes a halogen, a C₁₋₄ alkoxy groupor an NR₁R₂ group in which R₁ and R₂ are as defined above

[0013] to form a compound of the general formula (4)

[0014] in which Y, X₁, X₂ and B are as defined above, and, if B denotesa halogen or a C₁₋₄ alkoxy group, reacting the compound of the generalformula (4) with a compound of the general formula (5)

[0015] in which R₁ and R₂ are as defined above to form a compound of thegeneral formula (6)

[0016] in which Y, X₁, X₂, R₁ and R₂ are as defined above.

[0017] To form a compound of formula (1), the compound of formula (6)can be treated with a reducing agent. If desired, the compound offormula (1) thus obtained is converted into a salt.

[0018] It will be appreciated that if in formula (3) B denotes an NR₁R₂group in which R₁ and R₂ are as defined above, compound (6) instead ofcompound (4) is formed directly by reaction of compound (2) withcompound (3).

[0019] As set forth above compound (4) is prepared by reacting animidazopyridine of formula (2) with an oxalic acid derivative of formula(3). This reaction is conveniently carried out in an aprotic organicsolvent, for example n-hexane, cyclohexane, acetonitrile, acetone,ethylacetate, toluene, methyl tert. butyl ether or mixtures of thesesolvents, preferably a mixture of cyclohexane with toluene, at atemperature range from 0-100° C., preferably from 0-10° C., and in thepresence of an organic base, for example tertiary alkylamines, pyridineor substituted pyridines, preferably pyridine. If in formula (3) Bdenotes a halogen or a C₁₋₄ alkoxy group, the product (4) thus obtainedis subsequently reacted with a primary or secondary amine of formula(5), conveniently at a temperature range from 0-100° C., preferably from30-40° C. If in formula (3) B denotes an NR₁R₂ group, the reaction ofcompound (2) with compound (3) directly yields a compound of formula (6)instead of compound (4), and no intervening treatment with a compound offormula (5) is necessary.

[0020] The compound of formula (6) thus obtained is then reacted with anappropriate reducing agent to form compound (1). This reaction isconveniently carried out in a polar aprotic solvent, for examplepyridine, dimethylformamide or acetonitrile, preferably pyridine, in thepresence of an organic acid, for example acetic acid, formic acid ortoluenesulfonic acid, preferably acetic acid, and of an acylating agent,for example acetic anhydride or acetylchloride, preferably aceticanhydride, at a temperature range from 25-75° C., preferably from 50-55°C. A suitable reducing agent is, for example, Zn.

[0021] The compounds of the general formula (6) and their preparationalso form part of the present invention.

[0022] The following examples illustrate the invention in greaterdetail.

EXAMPLE 1 Preparation of6-methyl-N,N-dimethyl-2-(4-methylphenyl)imidazol[1,2-a]pyridine-3-glyoxyacetamide,compound (6)

[0023] To a slurry of 10.0 g (45 mmol) of6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine in a mixture of 20.0 gof toluene and 28.0 g of cyclohexane were added 8.6 (0.068 mmol) ofoxalylchloride within 15 minutes at 0-5° C. 3.6 g (45 mmol) of pyridinewere added within 5 minutes at 0-5° C. The resulting slurry was heatedto 65-70° C. and stirred for 2 hours. Then it was cooled to 30-35° C.and 8.4 g (187 mmol) of dimethylamine were introduced. To the slurrywere added 26.0 g of water and 2.3 g of isopropanol. The product wasisolated by filtration to afford the title compound in 80% yield.

EXAMPLE 2 Preparation ofN,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-yl]acetamide,compound (1)

[0024] To a slurry of 150.0 g (0.467 mol) of6-methyl-N,N-dimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-glyoxyacetamideand 105.0 g (1.605 mol) of zinc powder in 443.0 g of pyridine was addeda solution of 94.0 g (0.920 mol) of acetic anhydride in 472.5 g ofacetic acid within 20-25 minutes at a temperature below 45° C. Thesuspension was then heated to 50-55° C. and stirred for 25-30 hours.Unreacted zinc was filtered off and the filtrate was subjected to avacuum distillation. To the remaining oil 455.0 g of 25% aqueous ammoniasolution were added. The precipitated solid was collected by filtrationand purified by recrystallization in 800.0 g of methylisobutylketone.The title compound was afforded in 65.6% yield.

1. A process for preparing compounds of the general formula (6)

in which: Y denotes hydrogen, a halogen or a C₁₋₄ alkyl group X₁ and X₂denote, independently of each other, hydrogen, a halogen or a C₁₋₄alkoxy, C₁₋₆ alkyl, CF₃, CH₃S, CH₃SO₂ or NO₂ group and R₁ and R₂ denote,independently of each other, hydrogen or a C₁₋₅ alkyl group, with theproviso that R₁ and R₂ do not both denote hydrogen, which processcomprises reacting a compound of the general formula (2)

in which Y, X₁ and X₂, are as defined above with a compound of thegeneral formula (3)

in which: A denotes a halogen and B denotes a halogen, a C₁₋₄ alkoxygroup or an NR₁R₂ group in which R₁ and R₂ are as defined above to forma compound of the general formula (4)

in which Y, X₁ X₂ and B are as defined above and, if B denotes a halogenor a C₁₋₄ alkoxy group, reacting the compound of formula (4) with acompound of the general formula (5)

in which R₁ and R₂ are as defined above.
 2. A compound of the generalformula (6)

in which: Y denotes hydrogen, a halogen or a C₁₋₄ alkyl group X₁ and X₂denote, independently of each other, hydrogen, a halogen or a C₁₋₄alkoxy, C₁₋₆ alkyl, CF₃, CH₃S, CH₃SO₂ or NO₂ group and R₁ and R₂ denoteindependently of each other, hydrogen or a C₁₋₅ alkyl group, with theproviso that R₁ and R₂ do not both denote hydrogen.
 3. A process forpreparing a compound of the general formula (1)

in which: Y denotes hydrogen, a halogen or a C₁₋₄ alkyl group X₁ and X₂denote, independently of each other, hydrogen, a halogen or a C₁₋₄alkoxy, C₁₋₆ alkyl, CF₃, CH₃S CH₃SO₂ or NO₂ group and R₁ and R₂ denoteindependently of each other, hydrogen or a C₁₋₅ alkyl group, with theproviso that R₁ and R₂ do not both denote hydrogen, or a salt thereofwhich process comprises reducing a compound of the general formula (6)

in which Y, X₁, X₂, R₁ and R₂ are as defined above with an appropriatereducing agent and, if desired, converting the compound of formula (1)thus obtained into a salt.
 4. A process according to claim 3 wherein thereducing agent is Zn.
 5. A process according to claim 3 or claim 4wherein the reduction is carried out in pyridine, dimethylformamide,dimethylacetamide, acetonitrile or a derivative of any of these, in thepresence of acetic acid, formic acid or toluenesulfonic acid and of anacylating agent.
 6. A process according to claim 5 wherein the acylatingagent is acetic anhydride or acetylchloride.